As has been detailed throughout this issue, prenatal alcohol
exposure is a risk factor for many adverse physical and behavioral
outcomes. Growth retardation, including intrauterine growth restriction,
facial dysmorphology, and neurodevelopmental problems, are hallmarks of
fetal alcohol syndrome (FAS) and also are seen throughout the continuum
of fetal alcohol spectrum disorders (FASD). In addition to these
well-studied effects, other pregnancy and birth outcomes have been
linked to prenatal alcohol exposure. Although not typically regarded as
definitive indicators of either FAS or FASD, these complications
nonetheless have been shown in both animal and human studies to be
associated with prenatal alcohol exposure. This article reviews research
examining the role of prenatal alcohol exposure in spontaneous abortion,
stillbirth, preterm delivery, and sudden infant death syndrome (SIDS).
It provides a broad survey of the relevant literature and presents the
most reliable information regarding adverse outcomes associated with
prenatal alcohol exposure. The article therefore focuses on findings
with sufficient confirmatory data and general consensus regarding the
effects of prenatal alcohol exposure and presents only minimal detail on
how prenatal alcohol exposure may affect birth outcomes, as there are
many theories about potential mechanisms, which vary by outcome, and
have not been widely confirmed.

RESEARCH METHODS AND LIMITATIONS

When reviewing studies of the associations between prenatal alcohol
exposure and birth outcomes, it is important to understand the
limitations inherent in this type of research. First, alcohol
consumption data typically are collected via self-report because no
reliable biomarker currently is available. Given the increasing
awareness of the dangers of drinking during pregnancy and the consequent
social stigma, many women who consume alcohol are likely to either deny
use or significantly underreport the amount that they drink (Ernhart et
al. 1988). Thus, the entire distribution of alcohol consumption may be
shifted significantly lower than the actual values (Sokol 1980), making
determination of specific consumption thresholds difficult.
Consequently, statements about "safe" versus "risk"
levels of pregnancy alcohol consumption should be made with caution, and
no amount of alcohol consumption should be considered safe. Related to
this, an additional concern is that false denial of drinking will result
in some women who consume alcohol during pregnancy being classified as
nondrinkers. This misclassification can increase type II error (i.e.,
false negatives) by increasing risk outcomes in the group considered to
have no prenatal alcohol exposure, making it less likely that effects
that truly are present will be identified. Therefore, it is critical
that every effort be made to collect alcohol consumption information
using methods that maximize accurate disclosure. Such methods, which
include detailed recall of exact amounts over a specified period of time
as well as nonjudgmental questioning, have been refined over decades of
research and are used in reliable studies of this type.

A second factor affecting research on prenatal alcohol exposure is
the recent discovery that some women appear to have an increased
susceptibility to the deleterious effects of alcohol use during
pregnancy. Thus, what might represent a somewhat "safe" level
of pregnancy alcohol consumption for one woman may be incredibly risky
for another. Women over the age of 30 appear to have an especially
increased risk for poor pregnancy outcomes related to drinking during
pregnancy (Sokol et al. 2007), as do women of certain racial and ethnic
backgrounds. For example, African American infants have been found to be
especially susceptible to adverse effects of prenatal alcohol exposure
(Sokol et al. 1986). Research also is beginning to explore genetic
markers or mutations associated with increased susceptibility to
alcohol's effects (Warren and Li 2005). Consequently, determining a
risk threshold that applies generally is further complicated.

Still another issue to be aware of in studies of prenatal alcohol
exposure is how alcohol consumption is quantified. The vast majority of
studies record alcohol consumption in terms of the number of drinks. The
problem, however, is that different types of alcoholic beverages contain
different amounts of alcohol. In addition, even within a type of
beverage category, people have different ideas of how many ounces
constitute a drink. Research methods have been developed to calculate,
as accurately as possible, how much a person is drinking in terms of
ounces of absolute alcohol. In this case, a drink is defined as 0.5
ounces (or just over 14 grams) of absolute alcohol. Research
questionnaires and interviews ask for specific details about what is
consumed, including brand name and the sizes of the containers used for
poured drinks. In doing so, the number of drinks consumed is
standardized across similar research studies, and most of the current
studies that are regarded as reliable and valid use this type of
methodology.

Finally, alcohol consumption during pregnancy does not typically
occur in a vacuum. Women who drink during pregnancy are significantly
more likely to engage in other negative health behaviors, including
smoking and illicit drug use (Aliyu et al. 2009; Ebrahim and Gfroener
2003). In addition, pregnant women who drink alcohol are more likely to
have had multiple previous pregnancies; to be older, unmarried, and of
lower socioeconomic status; to experience greater levels of stress; and
to have a comorbid mental health condition (Caetano et al. 1998; Ebrahim
et al. 1998; King-Hele et al. 2009; Perreira and Cortes 2006; Rubio et
al. 2008). All of these associated factors have been shown to increase
the risk of poor pregnancy outcomes, including spontaneous abortion,
stillbirth, preterm delivery, and, in some cases, SIDS. Because of this,
it becomes difficult to point with certainty to alcohol consumption as a
proximate cause of these outcomes, even in studies with rigorous
multivariate control, as the increased risk may in fact be a result of
less precisely measured comorbid factors rather than a primary causal
link (Abel 1997).

Despite the limitations in studies of human prenatal alcohol
exposure, findings have been confirmed in animal studies without such
limitations, pointing to a causal association between prenatal alcohol
exposure and poor pregnancy outcomes and suggesting specific biological
mechanisms. However, such control clearly is not possible in human
studies. At best, studies can assess alcohol consumption as reliably as
possible and attempt to account for confounding factors through specific
sample selection or statistical methods of control. This is not always
easy, as many of the associated risk factors occur at very high rates in
pregnant drinkers. For example, 11.4 percent of pregnant women in the
United States smoke cigarettes (Martin et al. 2003), a known risk factor
for poor pregnancy outcomes. However, in a recent large-scale
epidemiological study, more than 55 percent of women who admitted to
drinking during pregnancy were smokers (Aliyu et al. 2009). Thus, it is
difficult to sample enough nonsmokers who consume alcohol who are truly
representative of drinkers in general. Statistical control also presents
a problem because after removing variance in pregnancy outcomes
attributed to smoking, often very little unique variance remains that
can be attributed to alcohol exposure. In addition, as also may be the
case for other risk factors, prenatal tobacco exposure has been shown to
synergize with prenatal alcohol exposure, together increasing the risk
of poor outcomes beyond the sum of the effects of either individually
(Odendaal et al. 2009).

Consequently, attributing poor birth outcomes to pregnancy alcohol
consumption is a complicated and ongoing task that requires continued
attention to validated methodology and to identifying specific
biological mechanisms. The studies reviewed in the sections below
generally are regarded as being adequately designed to produce valid
findings and make at least tentative causal inferences about the
association between prenatal alcohol exposure and birth outcomes.

SPONTANEOUS ABORTION

Spontaneous abortion, typically defined as fetal demise prior to 20
completed weeks of gestation, is the most common negative outcome of
pregnancy. Although many spontaneous abortions occur before the
pregnancy is known, clinically recognizable losses occur in as many as
20 percent of all pregnancies (Kline et al. 1989). The reason for the
fetal loss often is unknown; however, in some cases certain risk factors
are present. Alcohol exposure during pregnancy has been examined as one
potential risk factor for spontaneous abortion. As early as 1980,
research evidence suggested that drinking during pregnancy--at least
heavy drinking--was associated with a significantly increased rate of
spontaneous abortion (Sokol 1980). Women who consumed at least one
alcoholic beverage per day during pregnancy had more spontaneous
abortions, mainly during the second trimester, than did women who did
not drink or drank lesser amounts. Women who consumed more than three
drinks daily had a more than threefold increase in risk (Harlap and
Shiono 1980).

Recent attention has focused on more moderate levels of alcohol
consumption during pregnancy. In a large-scale prospective cohort study
(Windham et al. 1997) conducted in California in the early 1990s, women
who consumed more than three drinks per week during the first trimester
had a significantly increased risk of spontaneous abortion. In another
large-scale prospective study (Kesmodel et al. 2002a), this one
conducted in Denmark, women who consumed five or more drinks per week in
the first trimester had a fivefold increase in risk of first-trimester
spontaneous abortion. Researchers did not find an association between
alcohol intake during the second trimester and spontaneous abortion,
however. In another smaller Danish study (Rasch 2003), consumption of
five or more drinks per week was associated with a fivefold increase in
risk for spontaneous abortion. No association was found between
consumption of one to four drinks per week and spontaneous abortion. In
all three of these studies, effects remained significant after control
for potentially confounding factors, including age, parity,
socioeconomic status, and use of other substances.

It appears, then, that alcohol consumption during pregnancy, at
least at moderate to heavy levels, is linked to spontaneous abortion.
However, a review (Henderson et al. 2007) examining the impact of light
to moderate prenatal alcohol exposure concluded that there is no
consistent evidence for an increased risk of spontaneous abortion at
these lower levels of exposure. The studies described above also seem to
support that conclusion. These studies and others would appear to
suggest that the risk for spontaneous abortion is not increased unless
at least three drinks are consumed per week. However, as we detailed
above, caution should be exercised in drawing conclusions about
potential alcohol consumption thresholds based on these findings.

STILLBIRTH

Fetal demise occurring after 20 weeks gestation, or stillbirth,
affects 6.22 of every 1,000 pregnancies in the United States each year
(MacDorman et al. 2009). This pregnancy outcome may occur more
frequently among those who consume alcohol during pregnancy. Early
studies showed that alcohol intake of 14 or more drinks per week during
pregnancy was associated with stillbirth (Marbury et al. 1983). Kesmodel
and colleagues (2002b) demonstrated that consuming more than five drinks
per week led to a threefold increase in stillbirth risk, even after
adjustment for potentially confounding socioeconomic and lifestyle
factors. Animal studies also have demonstrated a fourfold increase in
stillbirth rates in conjunction with gestational alcohol administration
(Ba 2009).

A study (Aliyu et al. 2008) of more than 600,000 human births found
a statistically significant 40 percent increase in likelihood of
stillbirth for women who consumed any amount of alcohol compared with
those who did not consume alcohol at all. Data were further analyzed to
examine the amount of alcohol consumption, and the increased risk was
almost completely attributed to those who consumed five or more drinks
per week. Interestingly, women who reported drinking during pregnancy
but failed to provide information on the amount of consumption had the
highest risk of experiencing stillbirth. These women may in fact have
represented those with the highest levels of alcohol consumption,
providing further support for the hypothesis that responding according
to social desirability may have an impact on the accuracy of the data on
the amount of alcohol consumption during pregnancy. This study also
examined timing of stillbirth. Women were categorized by early
stillbirth (prior to 28 weeks' gestation) or later stillbirth.
Pregnancy alcohol consumption was significantly associated with early
(any drinking led to an 80 percent increase in risk) but not late (only
a nonsignificant 20 percent increase in risk) stillbirth. However, these
findings related to stillbirth timing may be a product of the particular
study sample, as timing of stillbirth was not an a priori hypothesis,
and further research may or may not explicate this particular finding.
Regardless, the findings from Aliyu and colleagues (2008) provide
additional confirmation of the link between prenatal alcohol exposure
and stillbirth described in earlier reports.

Although increased risk for stillbirth among women who consume
alcohol may be a result of associated socioeconomic and lifestyle
factors, the studies reported above controlled for many of these factors
and still found significant effects. Animal studies that have produced
associations between prenatal alcohol exposure and stillbirth further
support the idea that alcohol exposure is exerting a direct biological
effect that results in fetal demise, rather than identified effects
being attributed solely to associations between alcohol consumption and
other risk factors. Finally, a review (Burd et al. 2007) reported that
prenatal alcohol exposure has been shown to be associated with placental
dysfunction, decreased placental size, impaired blood flow and nutrient
transport, and endocrine changes, any of which could play a role in
stillbirth and in the alcohol exposure effects on preterm birth
described below.

PRETERM BIRTH

Preterm birth is typically defined as delivery occurring before 37
completed weeks of gestation. In the United States, there are nearly
half a million preterm deliveries each year, or 12.1 percent of all
births (Martin et al. 2003). Babies born prior to 37 weeks can be
further classified as mildly preterm (32 to 36 weeks) and extremely
preterm (less than 32 weeks). Nearly two dozen published studies have
examined the potential association between alcohol consumption during
pregnancy and preterm birth, and the assertion that a link does indeed
exist is controversial (Bailey and Sokol 2008). Many studies suffered
from methodological weaknesses, including small sample size, failure to
adequately control for confounding factors, inadequate assessment of
alcohol exposure, and unreliable gestational dating (i.e., using
menstrual cycle dates rather than ultrasound dating), and consequently
most reported no significant link between prenatal alcohol exposure and
preterm birth (Bailey and Sokol 2008). Two studies (Kesmodel et al.
2000; O'Leary et al. 2009) that primarily relied on ultrasound
dating to establish prematurity and controlled for many potentially
confounding factors both demonstrated an increased risk of preterm birth
associated with prenatal alcohol exposure. In one study (Kesmodel et al.
2000), consumption of 10 or more drinks per week was associated with a
nearly threefold increase in the risk of delivery prior to 37 weeks.
Consumption at lower rates was not significantly associated with preterm
delivery. In the other study (O'Leary et al. 2009), which also
found no link between low to moderate alcohol consumption and preterm
delivery, binge drinking at any point during pregnancy and heavy
drinking during the first trimester both predicted a two- to threefold
increase in risk in prematurity. However, some effects fell short of
statistical significance after controlling for confounding because of
small group sizes.

Two other studies with large samples, adequate control for
confounding factors, and reliable assessment of alcohol exposure and
gestational dating have examined the link between prenatal alcohol
exposure and different levels of prematurity. Adams and colleagues
(1995) examined preterm delivery risk factors among a cohort of Army
service women. Although gestational age at birth was not universally
obtained through ultrasound examination, it was the method available for
most women. Alcohol consumption at entry into prenatal care was
associated with a significant increase in extreme preterm delivery (29
to 32 weeks' gestation). Level of alcohol consumption was not
considered.

Sokol and colleagues (2007) conducted a large-scale study following
over 3,000 women prospectively for pregnancy substance use, with
ultrasound-confirmed pregnancy dating. Prenatal alcohol exposure was
associated with significantly increased risk of extreme preterm delivery
(less than 32 weeks) after controlling for potential confounders,
including the use of other substances, demographics, and clinical
factors. Specifically, based on risk estimates, if all women in the
sample had abstained from alcohol consumption during pregnancy, more
than two of every five preterm births would have been avoided. Prenatal
alcohol exposure also was associated with mild prematurity but only for
women over 30 years of age. The actual amount of alcohol consumption
needed in order to see an effect on preterm birth is not clear from this
study, as the number of days in which alcohol was consumed each week was
analyzed rather than total number of drinks. However, a repeat analysis
including women with methods of gestational age dating other than
ultrasound failed to detect an association between prematurity and
alcohol consumption. Thus, it appears that accurate dating of
gestational age examined at different levels of prematurity is crucial
in identifying associations between alcohol exposure and preterm birth,
and may explain why this effect has not been observed in other studies
(Bailey and Sokol 2008). It also appears that, at present, evidence for
increased risk in overall preterm birth attributed to low to moderate
levels of alcohol consumption during pregnancy is inconsistent
(Henderson et al. 2007). This could be caused by many factors, including
the fact that being born preterm reduces and/or eliminates alcohol
exposure during the third trimester, thus potentially reducing the
impact of exposure compared with what might have occurred had the
pregnancy gone to term. Additionally, a more definite risk profile does
emerge when alcohol consumption at higher levels is examined against
different levels of prematurity.

SIDS

Despite increased awareness and risk-reduction messages, SIDS
remains the leading cause of infant mortality in the United States,
occurring at a rate of 0.53 per 1,000 infants (Mathews and MacDorman
2006). In 2002, Iyasu and colleagues (2002) published the first report
detailing an association between prenatal alcohol exposure and SIDS.
Although prenatal tobacco exposure had long been thought to contribute
to SIDS, prenatal alcohol exposure had never been independently
associated with this outcome. Early pregnancy alcohol consumption at any
level was associated with a significantly increased risk of SIDS even
after controlling for other potential confounders. Similarly,
first-trimester binge drinking also was highly associated with SIDS in
the case--control study of 99 Plains Indians infants (Iyasu et al.
2002). Alcohol consumption later in pregnancy was not significantly
associated with the incidence of SIDS. In another study, infants who
died from SIDS were nearly twice as likely as those who died from other
causes to have had any prenatal alcohol exposure (Duncan et al. 2008).
This difference was not statistically significant because of the small
sample size and number of confounding factors. However, infants in SIDS
cases were more than three times as likely to have had exposure to binge
drinking prenatally, a difference that did reach statistical
significance.

Clearly, more studies with significantly larger samples are needed
before definitive conclusions about the association between prenatal
alcohol exposure and SIDS can be made, and the Prenatal Alcohol and SIDS
and Stillbirth Network is working to develop additional research on this
potentially causal link. In addition, recent studies on infant sleep
regulatory mechanisms lend further support to the possibility of an
association. In one small-scale study (Troese et al. 2008), infants of
mothers with the highest alcohol use estimates (median split) exhibited
atypical infant sleep state and movement parameters. These infants had
increased sleep fragmentation, with brief sleep episodes that were
interrupted after sleep onset by wakefulness, and significant reductions
in the duration of sleep-related spontaneous movements. Consistent with
the resultant developing sleep deprivation, prenatal alcohol exposure
also was significantly related to maternal reports of decreased infant
alertness and increased irritability. All of these sleep-related
parameters have been found to predict increased risk for SIDS in other
studies (Schectman et al. 1992).

CONCLUSIONS

Clearly, alcohol consumption during pregnancy has wide-reaching
effects. In addition to the more typically seen FAS and FASD outcomes,
many other adverse pregnancy and birth outcomes have been linked to
prenatal alcohol exposure. Although further research is needed, existing
studies suggest that drinking during pregnancy may increase the risk of
miscarriage, stillbirth, preterm delivery, and SIDS. It remains to be
seen whether these effects primarily are attributed to true biological
effects, sociodemographic and lifestyle factors that co-occur with
pregnancy drinking, or, most likely, a combination and possibly
synergistic effect. Animal studies, tightly controlled human studies,
and studies that have examined structural and chemical alterations would
suggest, at least in part, a direct physiological mechanism. Thus, it is
incumbent upon prenatal care providers to identify and address pregnancy
alcohol use with their patients. Brief, reliable screening tools are
available, and interventions with pregnant women to reduce or eliminate
their alcohol consumption are easy to implement and are known to be
effective. With these efforts, health care providers can help to reduce
the incidence and consequences of the preventable adverse effects that
are attributable to drinking during pregnancy.

KESMODEL, U.; WISBORG, K.; OLSEN, S.F.; ET AL. Moderate alcohol
intake during pregnancy and the risk of stillbirth and death in the
first year of life. American Journal of Epidemiology 155(4):305-312,
2002b. PMID: 11836194

BETH A. BAILEY, PH.D., is an associate professor, Department of
Family Medicine, East Tennessee State University, Johnson City,
Tennessee.

ROBERT J. SOKOL, M.D., is a distinguished professor, Department of
Obstetrics and Gynecology, and Director of the C.S. Mott Center for
Human Growth and Development, Wayne State University, Detroit, Michigan.